Abstract 4486: Stromal depletion by a docetaxel nanoparticle for enhanced therapy of breast and pancreatic cancer
Bibliographic record
Abstract
Abstract Tumor stroma consists of genetically normal cells that express abnormal phenotype in the tumor microenviroment, and are drivers of tumor cell proliferation and migration processes. Stromal cells can represent a significant fraction of tumor mass, and represent a barrier to drug delivery, given that stromal fibroblasts exert contractile forces which reduce vascular perfusion and increase interstitial fluid pressure. In the field, the stroma is widely recognized as a target for therapy, both to normalize the reactive microenvironment, and to reduce drug delivery barriers, but with limited clinical success. We have developed a nanoparticle delivery system for docetaxel (Cellax), a conjugate of carboxymethylcellulose and PEG, which condenses into well defined 120 nm particles suitable for intravenous administration. In addition to enhanced pharmacokinetics, 5-10X improved tumor uptake, and enhanced anti-tumor efficacy compared to approved taxanes such as native DTX (Taxotere) and nab-PTX (an albumin-paclitaxel nano-formulation, Abraxane), we have observed an anti-stromal effect in breast and pancreatic models. In a 4T1 orthotopic breast cancer model in mice, 85% of Cellax particles were taken up by cancer-associated fibroblasts (CAF), a major component of stroma. Further, in 4T1 and MDA-MB-231 breast models, Cellax treatments reduced CAF by 82 and 70% respectively, while native DTX and Nab-paclitaxel exerted no anti-stromal activity. Concomitant effects were ∼70-fold increased perfusion, ∼3-fold decreased interstitial fluid pressure (IFP), and a 7-24 fold reduction in lung metastases. In a primary human pancreatic xenograft model (OCIP19), we measured a 50% reduction in αSMA+ cells (activated pancreatic stellate cells) and macrophage within 1 day of Cellax treatment, while nab-PTX only decreased the macrophage population 3-7 days post therapy. In addition, vascular perfusion in the Cellax treated pancreatic tumor was increased 12X relative to nab-PTX and control treatment groups, with significantly reduced metastases. Preliminary mechanistic studies indicate that albumin absorbs to Cellax particles, promoting interaction with SPARC-expressing stromal cells, leading to stroma-specific activity. Citation Format: Mark Ernsting, Mami Murakami, Elijus Undzys, Shyh-Dar Li. Stromal depletion by a docetaxel nanoparticle for enhanced therapy of breast and pancreatic cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4486. doi:10.1158/1538-7445.AM2014-4486
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".